Alzheimer's disease (AD) is a devastating neurodegenerative disorder that afflicts millions of people worldwide. Two major features of AD are: (1) degeneration of basal forebrain cholinergic neurons and ensuing deficient cholinergic functions in cortex and hippocampus; (2) extracellular protein aggregates containing beta-amyloid peptides (Abeta) in these cholinergic target areas. So far, the most effective therapeutic strategy in AD treatment is to enhance cholinergic transmission. Neuromodulatory functions of the cholinergic system are mainly mediated by muscarinic receptors (mAChRs). It has long been recognized that mAChRs are crucial for the control of high-level cognitive processes. Drugs that activate mAChRs are helpful in ameliorating cognitive deficits of AD. Despite the discovery of correlation between cholinergic hypofunction and AD, the cellular and molecular mechanisms underlying the function and dysfunction of mAChRs in normal cognition and dementia remain elusive. The long-term goals of this project are to understand (1) how muscarinic signaling is involved in the regulation of neuronal activity and synaptic transmission in frontal cortex, which is critical for learning and memory under normal condition; and (2) how this regulation is altered in animal models that simulate cognitive and memory impairments associated with AD. Recent evidence indicates that GABAergic inhibition in frontal cortex plays an important role in "working memory" by controlling the timing of neuronal activities during cognitive operations. We hypothesize that the GABAA receptor channel is potentially a key cellular substrate for muscarinic signaling in cognition and memory, and disruption of its regulation by mAChRs in AD might contribute to the cognitive impairment. Transgenic mice overexpressing a mutant gene for beta-amyloid precursor protein (APP) show behavioral and histopathological abnormalities resembling AD, and therefore will be used as an AD model in our experiments. Emerging evidence suggests that Abeta plays pleiotropic roles in the regulation of cholinergic functions in cortex. We hypothesize that the muscarinic modulation of GABAA receptor function is lost in AD models due to the interference of Abeta on muscarinic signaling. Combined electrophysiological, pharmacological, biochemical and molecular analyses will be used to test these hypotheses. This research would shed some light on how the two prominent features of AD (cholinergic hypofunction and Abeta accumulation) may be linked to cause cognitive impairments. Such knowledge should offer important insights into the cellular and molecular basis of AD and the development of new pharmacological agents in the treatment of this disease.